Evidence for morphine and morphine-like alkaloid responses resistant to naloxone blockade in the rat vas deferens.

The application of morphine or surrogates to the isolated rat vas deferens maintained at 37° C in Tyrode solution, produced an increase in the electrically induced muscular twitch. In contrast, leucine enkephalin or D-alanine₂methionine enkephalinamide produced a dose-dependent inhibition of the muscular twitch. The effect of morphine and derivatives was not antagonized by naloxone, but the depression caused by the opiate pentapeptides or β-Endorphin was readily antagonized and reversed by naloxone. Tolerance developed to the $\text{in vitro}$ effect of morphine; vasa deferentia obtained from tolerant-dependent rats were about six times less sensitive to the effect of morphine and about five times less sensitive to the depression caused by leucine enkephalin as compared to their respective paired, placebo implanted control rats.     

Suppression of appetitive behavior in the rat by naloxone: lack of effect of prior morphine dependence

Naloxone (0.3–10 mg/kg) produced a dose-related suppression of eating and drinking in rats that had been deprived of food for 48 hr or water for 24 hr. The suppression of water intake by naloxone was unaltered in rats that had been physically dependent upon morphine one week earlier and which were tolerant to the analgesic effect of morphine at the time naloxone was tested. These results confirm the ability of naloxone to suppress appetitive behavior in the rat but do not resolve the issue of whether or not this effect of naloxone is the consequence of an interaction with an endogenous opioid system.     

Footshock induced analgesia in mice: its reversal by naloxone and cross tolerance with morphine

Using the abdominal constriction response as the criterion for analgesia, mice tested immediately after a period of footshock showed a significant analgesic response compared with non-footshocked controls. Footshock induced analgesia could not be elicited in mice that had been made tolerant to morphine or in mice that had been pretreated with the narcotic antagonist naloxone. It is concluded that footshock induced analgesia in the mouse is due to the release of endogenous opioid peptides.     

Tolerance to morphine induced by chronic mild environmental stressors

Pain-sensitivity as well as the analgesic and thermoregulatory effects of morphine were studied after two different types of chronic environmental stresses in rats (extra stimulation of newborns for 21 days, or social isolation for a month in adult age). The basal pain sensitivity and the base-line body temperature were similarly affected after the two interventions: an increased tail-flick latency, a decreased hot-plate latency and a decreased body temperature were noted. The analgesic and thermoregulatory effects of morphine were uniformly reduced in rats exposed to either stress. These findings suggest a common effect of various non painful mild environmental stresses on the activity of the endogenous opioid system.     

Transfer of morphine across the human placenta and its interaction with naloxone

The purpose of this investigation was to measure the transfer rate and clearance of morphine across the placenta with and without naloxone. Term human placental cotyledons were perfused in vitro. The placenta was perfused with 50 ng/mL of morphine in the absence (n=4) and presence (n=5) of 100 ng/mL of naloxone. Maternal and fetal samples were collected. Student's t-test or one-way repeated measures ANOVA were used for all comparisons. The maternal-to-fetal morphine transfer rate was 0.73+/-0.44 ng/mL/min in the morphine and 0.69+/-0.26 ng/mL/min in the morphine-naloxone experiments (p=0.89). The clearance of morphine was 0.89+/-0.39 mL/min without naloxone and 0.87+/-0.27 mL/min with naloxone (p=0.92). Final morphine concentrations in the morphine experiments were 9.78+/-6.17 ng/mL (maternal) and 3.43+/-2.14 ng/mL (fetal) and 10.04+/-3.89 ng/mL (maternal) and 4.16+/-1.64 ng/mL (fetal) in the morphine-naloxone experiments. Morphine readily crosses the term human placenta. Naloxone does not alter placental transfer or clearance of morphine, suggesting that transfer across the placental barrier is not altered by changes in vascular resistance. Placental retention of morphine prolongs fetal exposure to morphine.     

Habituation in the crabChasmagnathus granulatus: effect of morphine and naloxone

Summary The escape response decrement shown by the crabChasmagnathus granulatus as a consequence of repeated shadow presentation, meets five of the seven tested parametric criteria of habituation. Results concerning stimulus generalization and dishabituation strongly suggest that neither motor fatigue nor sensory adaptation can account for the response waning. The effects of morphine and naloxone on performance were also studied. Neither 50 nor 5 g morphine/g exerted any modulatory effect on memory retention. A dose of 50 g morphine/g produced an anterograde detrimental effect on responsiveness but no long-term training effects could be detected after the drug's period of action. A dose of naloxone of 1.6 g/g did not antagonize the effect of morphine. The potential value of the response habituation as a model for studying both habituation dynamics and the mechanisms that subserve it, and also for elucidating the effects of opiates on this memory process, is discussed.Abbreviations ANOVA analysis of variance - d.w. distilled water - ITI intertriai interval - LOR large opaque rectangle - M P morphine-HCl - NX naloxone - S1 first trial session - S2 second trial session - S3 third trial session - S4 fourth trial session - S5 fifth trial session - SOR small opaque rectangle - STR small translucent rectangle     

Acupuncture analgesia in rats and its changes under the effect of morphine and naloxone

It was established in chronic experiments on rats that electric acupuncture of the acupuncture point noticeably decreases pain reaction to electric stimulation of the tail. Morphine given in a subanalgetic dose (5 mg/kg) potentiated acupuncture analgesia, while 5 mg/kg of naloxone completely abolished it. Potential mechanisms of analgesia realization during electric acupuncture are discussed.     

Comparison between naloxone reversal of morphine and electrical stimulation induced analgesia in the rat mesencephalon

Comparisons were made between the efficacy of naloxone to reverse analgesia induced by electrical stimulation (SPA) of the periaqueductal gray matter and analgesia induced by microinjections of morphine into the same brain region. Naloxone at 1 or 10 mg/kg was ineffective in antagonizing SPA during the first two minutes post-stimulation. Although some antagonism did appear 3–5 minutes after stimulation, the effect was neither consistent nor dose-dependent. Morphine, on the other hand, was antagonized in a dose-dependent and complete fashion by naloxone. The assumption that similar mechanisms underlie both opiate and electrical stimulation induced analgesia is discussed.     

Differential effects on morphine analgesia and naloxone antagonism by biogenic amine modifiers.

The stimulation of dopaminergic receptors, inhibition of serotonin synthesis or blockade of muscurinic receptors by various modifiers led to inhibition of morphine analgesia in mice. Blockade of dopaminergic receptors or the increase in serotonergic or cholinergic activity resulted in the enhancement of morphine analgesia. Serotonergic and cholinergic systems are proposed as positive and the dopaminergic system as negative modulators of morphine analgesia. The modulation of naloxone antagonism was much more complicated than that of morphine analgesia and often the effect of biogenic amine-modifiers on antagonism differed from that on analgesia. The fact that biogenic amine-modifiers do not affect morphine analgesia and naloxone antagonism by a similar pattern suggest that interaction of narcotics and narcotic antagonists with analgesic receptors may not be exactly the same.     

Long-term changes in self-stimulation threshold by repeated morphine and naloxone treatment

To analyse the interaction between endogenous opioid systems and brain reward, the influence of repeated treatment for 3 weeks with morphine and the opioid antagonist naloxone was investigated in rats with self-stimulation electrodes in the ventral tegmental area. Changes in threshold of self-stimulation determined by a response rate insensitive two lever method were considered as changes in reward. Morphine induced a temporary decrease of the response rate which lasted 3 days, and decreased the threshold for self-stimulation. The effect on threshold remained present till morphine treatment was discontinued, indicating that tolerance does not develop to this effect of morphine. Repeated naloxone treatment gradually increased the threshold for self-stimulation. This effect persisted after discontinuation of naloxone treatment. It is concluded that blockade of opioid receptors induces long term changes in the setpoint of self-stimulation reward.     

Effects of morphine or naloxone on kainic acid neurotoxicity.

Intraperitoneal or subcutaneous administration of kainic acid (KA) (5–15 mg/kg) to adult rats included a syndrome of wef wet dog shakes (WDS), convulsions and brain damage. Components of the syndrome were evoked in a dose-related manner with low doses inducing WDS only and progressively higher doses being associated with an increasing incidence of naloxone (4 mg/kg) 5 minutes prior to KA (12 mg/kg) resulted in a moderate reduction in the incidence of WDS, convulsions and brain damage. Administering morphine (5 or 10 mg/kg) 10 minutes prior to KA (7 mg/kg) markedly enhanced the neurotoxicity of KA as was evidenced in an increase in the incidence of convulsions and brain damage from 7% (KA alone) to 100% (morphine + KA). KA, a structural analog of the putative excitatory transmitter glutamate (Glu), is thought to exert its excitotoxic activity through Glu excitatory receptors. Additional studies are needed to elucidate the mechanism by which morphine and naloxone respectively enhance and suppress KA neurotoxicity and to clarify whether interaction of these agents at either opioid or Glu receptors plays a role in such phenomena.     

Tolerance to morphine analgesia and immobility measured in rats by changes in log-dose-response curves

Using the bar and tailflick tests, morphine log-dose-response (LDR) curves were determined for immobility and analgesia, respectively, in male Wistar rats following 15 daily i.p. injections of 0, 20, or 200 mg/kg of morphine sulfate. The LDR curves for the two measures were qualitatively similar. Chronic morphine treatment resulted in a shift to the right and flattening of both curves. These results indicate that the flattening of the LDR curve in morphine tolerant rats is general to a number of opiate effects, and raise the possibility that both morphine-produced immobility and analgesia are subserved, in part, by a similar mechanism. In addition, after a test dose of 900 mg/kg, more rats in the 20 mg/kg than in the 200 mg/kg treatment group died of convulsions. Thus, tolerance developed to lethality produced by the convulsive effects of opiates.     

Changes in morphine self-administration in rats induced by prostaglandin E1 and naloxone

Interactions of prostaglandin E₁ (PGE₁) with morphine have been reported in several test systems and an hypothesis has been advanced for a role of prostaglandins in morphine analgesia and physical dependence. In rats self-administering morphine intravenously, a simultaneous and continuous infusion of naloxone hydrochloride at 56 to 560 μg/kg/day caused the expected increase in injection rate for morphine. Infusion of PGE₁ by itself at 56 or 180 μg/kg/day had no effect on the rate of morphine intake. Likewise the addition of PGE₁ at 180 μg/kg/day did not potentiate the increase caused by naloxone (56 or 180 μg/kg/day) when it was added to the naloxone infusion. These results do not support a role for prostaglandins in the behavioral aspects of morphine addiction. However, larger doses of PGE₁ (1 and 1.8 mg/kg/day), which were without overt effects in normal rats, caused severe and incapacitating prostration in morphinized rats.     

Effects of morphine and naloxone on fetal heart rate and movement in the pig.

To test the hypothesis that an increasing opioid tonus is involved in decreases in fetal heart rate (FHR) and movement (FM) during late gestation, we studied the effects of intravenous bolus injections of morphine (1 mg) and naloxone (1 mg) on FHR and FM in the fetal pig. Twenty-one fetuses (1 per sow) were catheterized at 90-104 days of gestation (median 100 days). Recordings of FHR (electrocardiograph or Doppler-derived signals) and FM (ultrasonography) were made from 15 min before to 45 min after treatment. Morphine administration significantly decreased FHR, but it increased FHR variation and forelimb movements (LM). LM were clustered, and this stereotyped behavior has never before been observed in any mammalian fetus. Naloxone administration increased gross body movements and FHR without significant changes in FHR variation. It is concluded that FHR and motility are under opioidergic control in the pig fetus. Both morphine and naloxone induce hypermotility, suggesting that naloxone does not act as a pure opioid antagonist in the fetal pig.